Inhibition of insulin- and insulin-like growth factor-I-stimulated growth of human breast cancer cells by 1,25-dihydroxyvitamin D-3 and the vitamin D-3 analogue EB1089

1,25 Dihydroxyvitamin D-3 (1,25-(OH)(2)D-3) and a number of synthetic vitamin D-3 analogues with low calcaemic activity, have been shown to inhibit breast cancer cell growth in vitro as well as in vivo. The purpose of the present study was to investigate a possible interaction of 1, 25-(OH)(2)D-3 and the vitamin D-3 analogue EB1089 with the insulin-IGF-I regulatory system. The oestrogen receptor-positive MCF-7 human breast cancer cells used in this study are able to grow autonomously and their growth is stimulated by insulin. In order to avoid interference of IGF-binding proteins (IGF-BPs), we used an analogue of IGF-I, long R(3) IGF-I, which stimulated MCF-7 cell growth similar to insulin. The growth stimulation by insulin and by long R(3) IGF-T was completely inhibited by 1,25-(OH)(2)D-3 and EB1089. Autonomous growth was also inhibited by 1,25-(OH)(2)D-3 and EB1089. The analogue EB1089 was active at 50 times lower concentrations than 1,25-(OH)(2)D-3. It was shown that growth inhibition was not achieved through downregulation of insulin and IGF-I binding after 48 h. Paradoxically, after prolonged treatment (8 days), an upregulation of insulin and IGF-I binding was observed. Two possible intracellular mediators of the insulin-IGF mitogenic signal are C-FOS and mitogen-activated protein (MAP) kinase. Insulin-induced C-FOS mRNA was inhibited by 1,25-(OH)(2)D-3, suggesting that it could be involved in the growth inhibition by 1,25-(OH)(2)D-3. MAP kinase activation appeared not to be involved in growth stimulation by both insulin and IGF-I. Together, the present study demonstrates that vitamin D-3 compounds can block the mitogenic activity of insulin and IGF-I, which may contribute to their tumour suppressive activity observed in vivo. Copyright (C) 1996 Elsevier Science Ltd